A highly tumor-targeted nanoparticle of podophyllotoxin penetrated tumor core and regressed multidrug resistant tumors

Podophyllotoxin (PPT) exhibited significant activity against P-glycoprotein mediated multidrug resistant (MDR) tumor cell lines; however, due to its poor solubility and high toxicity, PPT cannot be dosed systemically, preventing its clinical use for MDR cancer. We developed a nanoparticle dosage form of PPT by covalently conjugating PPT and polyethylene glycol (PEG) with acetylated carboxymethyl cellulose (CMC-Ac) using one-pot esterification chemistry. The polymer conjugates self-assembled into nanoparticles (NPs) of variable sizes (20–120 nm) depending on the PPT-to-PEG molar ratio (2–20). The conjugate with a low PPT/PEG molar ratio of 2 yielded NPs with a mean diameter of 20 nm and released PPT at ∼5%/day in serum, while conjugates with increased PPT/PEG ratios (5 and 20) produced bigger particles (30 nm and 120 nm respectively) that displayed slower drug release (∼2.5%/day and ∼1%/day respectively). The 20 nm particles exhibited 2- to 5-fold enhanced cell killing potency and 5- to 20-fold increased tumor delivery compared to the larger NPs. The biodistribution of the 20 nm PPT-NPs was highly selective to the tumor with 8-fold higher accumulation than all other examined tissues, while the larger PPT-NPs (30 and 120 nm) exhibited increased liver uptake. Within the tumor, >90% of the 20 nm PPT-NPs penetrated to the hypovascular core, while the larger particles were largely restricted in the hypervascular periphery. The 20 nm PPT-NPs displayed significantly improved efficacy against MDR tumors in mice compared to the larger PPT-NPs, native PPT and the standard taxane chemotherapies, with minimal toxicity.     

Protective effect of bromelain on corrosive burn in rats

IntroductionIn some cases, the tongue and oesophagus tissues are damaged by the corrosive burn. Surgical interventions may cause scar formation, and severe burns treatment methods are limited. This study aims to investigate bromelain, a phytotherapeutic product, on the corrosive burn as a non-surgical option and as an adjunctive therapy, insofar as the treatment of corrosive wounds is not limited only to the treatment of oxidative stress and inflammatory reactions.MethodsOn the tongues of Wistar albino rats, chemically produced oral ulcers were created by topical application of NaOH (40%) solution, and in the distal oesophagus same mixture was applied to produce a corrosive oesophageal burn. For a week, they were treated orally by bromelain (100 mg/kg/day) or saline solution. At the end of seven days, animals were decapitated to remove the tongue and oesophagus, and blood samples were collected to obtain serum. Myeloperoxidase (MPO) activity, malondialdehyde (MDA), glutathione (GSH), interleukin-1 beta (IL-1β) and tumour necrosis factor-alpha (TNF-α) concentrations were measured in serum, and luminol and lucigenin chemiluminescence (CL) were measured in tissue samples.ResultsMDA and CL values were significantly increased, and GSH levels in tissue significantly decreased due to the corrosive burns. Saline treated corrosive burn group measured higher in the serum cytokines in according to the control group.ConclusionsBromelain administration decreased oxidant and inflammatory parameters and increased antioxidant levels in NaOH-induced corrosive burns. Thus, we concluded that bromelain may protect the tongue and oesophagus tissues with its anti-inflammatory and antioxidant effects.